scholarly journals Evidence that microtubules do not mediate opsin vesicle transport in photoreceptors.

1989 ◽  
Vol 109 (6) ◽  
pp. 3053-3062 ◽  
Author(s):  
D K Vaughan ◽  
S K Fisher ◽  
S A Bernstein ◽  
I L Hale ◽  
K A Linberg ◽  
...  
Keyword(s):  
Outer Segment ◽  
Lucifer Yellow ◽  
Lateral Displacement ◽  
Linear Increase ◽  
Rod Photoreceptor ◽  
Drug Induced ◽  
Membrane Assembly ◽  
Induced Changes ◽  
Vectorial Transport

The organization of the rod photoreceptor cytoskeleton suggests that microtubules (MTs) and F actin are important in outer segment (OS) membrane renewal. We studied the role of the cytoskeleton in this process by first quantifying OS membrane assembly in rods from explanted Xenopus eyecups with a video assay for disc morphogenesis and then determining if the rate of assembly was reduced after drug disassembly of either MTs or F actin. Membrane assembly was quantified by continuously labeling newly forming rod OS membranes with Lucifer Yellow VS (LY) and following the tagged membranes' distal displacement along the OS. LY band displacement displayed a linear increase over 16 h in culture. These cells possessed a longitudinally oriented network of ellipsoid MTs between the sites of OS protein synthesis and OS membrane assembly. Incubation of eyecups in nocodazole, colchicine, vinblastine, or podophyllotoxin disassembled the ellipsoid MTs. Despite their absence, photoreceptors maintained a normal rate of OS assembly. In contrast, photoreceptors displayed a reduced distal displacement of LY-labeled membranes in eyecups treated with cytochalasin D, showing that our technique can detect drug-induced changes in basal rod outer segment assembly. The reduction noted in the cytochalasin-treated cells was due to the abnormal lateral displacement of newly added OS disc membranes that occurs with this drug (Williams, D. S., K. A. Linberg, D. K. Vaughan, R. N. Fariss, and S. K. Fisher. 1988. J. Comp. Neurol. 272:161-176). Together, our results indicate that the vectorial transport of OS membrane constituents through the ellipsoid and their assembly into OS disc membranes are not dependent on elliposid MT integrity.

GDP binding to rat brown fat mitochondria: effects of thyroxine at different ambient temperatures

1981 ◽  
Vol 241 (3) ◽  
pp. C134-C139 ◽  
Author(s):  
U. Sundin
Keyword(s):  
Linear Increase ◽  
Reciprocal Relationship ◽  
Brown Fat ◽  
Hormone Activity ◽  
Ambient Temperatures ◽  
Heating Capacity ◽  
Brown Adipose ◽  
Induced Changes ◽  
Brown Fat Mitochondria

Reports on a reciprocal relationship between sympathetic-nerve and experimentally induced changes in thyroid-hormone activity called into question the proposed role of thyroxine in the changes seen in the brown fat after cold adaptation. Rats reared at +30, +22, and +5 degrees C received daily injections of thyroxine (1 mg/kg). After 3 wk of treatment, the thermogenic state of the tissue was assessed by measuring the capacity of the brown fat mitochondria to bind guanosine 5'-diphosphate (GDP). GDP-inhibited mitochondrial swelling, brown adipose tissue (BAT) wet weights, and mitochondrial yields were also measured. The control animals showed a linear increase in GDP binding between +30 and +5 degrees C. Thyroxine was found to lower the GDP binding markedly at +5 degrees C, less so at +22 degrees C, while no effect was evident at +30 degrees C. The values at +22 and +30 degrees C were identical. The other parameters studied all confirmed these results. The conclusion made is that the thyroxine-induced rise in basal metabolic rate lowers the critical temperature and reduces the demand for nonshivering thermogenesis. This is reflected in the reduced GDP binding and hence heating capacity of the brown fat mitochondria.

scholarly journals Dysfunction of Heterotrimeric Kinesin-2 in Rod Photoreceptor Cells and the Role of Opsin Mislocalization in Rapid Cell Death

2010 ◽  
Vol 21 (23) ◽  
pp. 4076-4088 ◽  
Author(s):  
Vanda S. Lopes ◽  
David Jimeno ◽  
Kornnika Khanobdee ◽  
Xiaodan Song ◽  
Bryan Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Outer Segment ◽  
Photoreceptor Cell ◽  
Photoreceptor Cells ◽  
Cell Loss ◽  
Rod Photoreceptor ◽  
Retinal Degenerations ◽  
Cell Counts ◽  
And Function

Due to extensive elaboration of the photoreceptor cilium to form the outer segment, axonemal transport (IFT) in photoreceptors is extraordinarily busy, and retinal degeneration is a component of many ciliopathies. Functional loss of heterotrimeric kinesin-2, a major anterograde IFT motor, causes mislocalized opsin, followed by rapid cell death. Here, we have analyzed the nature of protein mislocalization and the requirements for the death of kinesin-2-mutant rod photoreceptors. Quantitative immuno EM showed that opsin accumulates initially within the inner segment, and then in the plasma membrane. The light-activated movement of arrestin to the outer segment is also impaired, but this defect likely results secondarily from binding to mislocalized opsin. Unlike some other retinal degenerations, neither opsin–arrestin complexes nor photoactivation were necessary for cell loss. In contrast, reduced rod opsin expression provided enhanced rod and cone photoreceptor survival and function, as measured by photoreceptor cell counts, apoptosis assays, and ERG analysis. The cell death incurred by loss of kinesin-2 function was almost completely negated by Rho−/−. Our results indicate that mislocalization of opsin is a major cause of photoreceptor cell death from kinesin-2 dysfunction and demonstrate the importance of accumulating mislocalized protein per se, rather than specific signaling properties of opsin, stemming from photoactivation or arrestin binding.

Microrna Expression and Drug-Induced Changes in Gene Expression Correlate with Ara-C Chemosensitivity in AML Cell Lines

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3623-3623 ◽  
Author(s):  
Neha S Bhise ◽  
Vishal Lamba ◽  
Jatinder Lamba
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Mirna Expression ◽  
Risk Group ◽  
Risk Groups ◽  
Drug Induced ◽  
Preliminary Results ◽  
Ic50 Values ◽  
Induced Changes

Abstract Abstract: Acute myeloid leukemia (AML) is a heterogeneous disorder, which is characterized by chromosomal abnormalities and genetic alterations. Cytarabine (Ara-C) is the most commonly used nucleoside analog for treatment of AML. However, the use of Ara-C is associated with two important clinical complications namely, inter-patient variability in response and development of intrinsic resistance. The inter-patient variability in response can be partly associated with polymorphisms in proteins that are required for intracellular uptake and activation of Ara-C to its phosphorylated form. Apart from genetic polymorphisms, expression of proteins involved in the uptake, activation, and inactivation of Ara-C have been shown to correlate with the overall patient survival. Over the past decade, various studies have identified microRNAs as important post-transcriptional regulators of gene expression. However, there are no studies till date that have identified key miRNAs involved in regulation of Ara-C pathway genes. Identification of these miRNAs will help in targeting these miRNAs to further understand inter-patient differences in gene expression. Additionally, drugs can also influence gene expression. However, there is critical gap in literature regarding role of Ara-C in inducing changes in gene expression. Understanding the dynamics of gene expression due to miRNAs and drug-induced changes would help open new opportunities for development of improved treatment strategies. Thus, the objective of this study is to understand the role of microRNAs in altering cytarabine cytotoxicity by influencing expression of pharmacokinetics (PK) and pharmacodynamics (PD) genes (n=18) in AML cell lines representing different risk groups. We evaluated genome-wide miRNA expression in 7 AML cell lines from different risk groups (favorable risk group: Kasumi-1, ME-1; intermediate risk group: AML-193, KG-1; adverse risk group: HL-60, MV-4-11, MOLM-16). We also evaluated the impact of cytarabine-induced gene expression changes in these AML cell lines. The gene expression changes were correlated with the in vitro chemosensitivity. Our preliminary results indicate that there was a significant correlation between the baseline miRNA expression for 16 miRNAs and Ara-C IC50 values (selected shown in Figure 1). We also observed that 57 microRNAs were associated with gene expression levels of the selected 18 Ara-C pharmacogenes (selected shown in Figure 1). Four miRNAs (miR-425-5p, miR-517a-3p, miR-519b-5p+hsa-miR-519c-5p, miR-522-3p) were found to be significantly associated with both gene expression and Ara-C IC50 values. We found that there were significant changes in gene expression of Ara-C pathway genes following treatment with 1uM or 10uM Ara-C. Briefly, there were significant changes in DCK, SLC29A1, CTPS1, CMPK1, NME1 and XRCC1 expression when treated with 10uM Ara-C and RRM2, NME1 and XRCC1 expression when treated with 1uM Ara-C. In conclusion, drug-induced changes in gene expression and miRNAs expression were found to correlate with chemosensitivity of AML cell lines. The preliminary results from our study help provide an insight into potential/additional molecular mechanisms associated with resistance observed in AML patients. Such knowledge is clinically significant, as identification of factors that contribute to the variable drug response would help in understanding and thus improving the variability in efficacy associated with cytarabine therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mechanisms of antiarrhythmic drug-induced changes in defibrillation threshold: Role of potassium and sodium channel conductance

1996 ◽  
Vol 27 (6) ◽  
pp. 1534-1542 ◽  
Author(s):  
Michael R. Ujhelyi ◽  
Michael Schur ◽  
Thomas Frede ◽  
Michael B. Bottorff ◽  
Marjorie Gabel ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Antiarrhythmic Drug ◽  
Defibrillation Threshold ◽  
Channel Conductance ◽  
Drug Induced ◽  
Induced Changes

scholarly journals The Role of Cerebral Metabolism in Determining the Local Cerebral Blood Flow Effects of Volatile Anesthetics: Evidence for Persistent Flow-Metabolism Coupling

1989 ◽  
Vol 9 (3) ◽  
pp. 323-328 ◽  
Author(s):  
Thomas D. Hansen ◽  
David S. Warner ◽  
Michael M. Todd ◽  
Laverle J. Vust
Keyword(s):  
Cerebral Metabolism ◽  
Local Cerebral Blood Flow ◽  
Halothane Anesthesia ◽  
Drug Induced ◽  
Experimental Conditions ◽  
Isoflurane Anesthesia ◽  
Flow Effects ◽  
Subcortical Regions ◽  
Induced Changes

The effects of equipotent doses of halothane (1.05%) versus isoflurane (1.38%) anesthesia on CMRglc were determined autoradiographically using the 2-[14C]deoxyglucose technique in the rat. Eight anatomically standardized coronal sections were selected and digitized from the autoradiographs. Mean CMRglc was determined for hemispheric, neocortical, and subcortical regions at each anatomic level, and a neocortical/subcortical CMRglc ratio was calculated. In addition, the current CMRglc autoradiographs, as well as previous CBF autoradiographs obtained under identical experimental conditions were examined to characterize and compare flow/metabolism relationships for the two anesthetics. For this analysis, CBF was determined in 80 selected anatomic areas, and the values from each area were plotted against CMRglc values obtained from identical areas. In all major regions, mean CMRglc was greater with halothane than with isoflurane. The neocortical/subcortical ratio, reflecting the pattern of CMRglc distribution, was also greater during halothane anesthesia. This suggests that isoflurane has a disproportionate effect on neocortical metabolism resembling patterns previously seen for CBF. Analysis of CBF versus CMRglc plots for each anesthetic group showed two parallel lines with nearly identical slopes, but different Y intercepts. We conclude that the distribution of CMRglc observed during 1 MAC (minimum alveolar concentration) halothane and isoflurane anesthesia parallels the distribution of CBF. This finding supports the conclusion that flow-metabolism coupling is intact during halothane and isoflurane anesthesia, and that drug induced changes in cerebral metabolism may play an important role in determining the CBF response to that drug. Furthermore, there is evidence that, at a given level of CMRglc, isoflurane may have greater vasodilating capabilities than halothane.

scholarly journals Global Approaches to the Role of miRNAs in Drug-Induced Changes in Gene Expression

2012 ◽  
Vol 3 ◽  
Author(s):  
Jodi E. Eipper-Mains ◽  
Betty A. Eipper ◽  
Richard E. Mains
Keyword(s):  
Gene Expression ◽  
Drug Induced ◽  
Induced Changes

scholarly journals The role of liver tryptophan pyrrolase in the opposite effects of chronic administration and subsequent withdrawal of drugs of dependence on rat brain tryptophan metabolism

1981 ◽  
Vol 196 (1) ◽  
pp. 161-170 ◽  
Author(s):  
A A Badawy ◽  
N F Punjani ◽  
M Evans
Keyword(s):  
Chronic Administration ◽  
Tryptophan Metabolism ◽  
Chronic Morphine ◽  
Drug Induced ◽  
Tryptophan Pyrrolase ◽  
Subsequent Withdrawal ◽  
Induced Changes ◽  
Phenazine Methosulphate ◽  
The Brain

1. Chronic administration of morphine, nicotine or phenobarbitone has previously been shown to inhibit rat liver tryptophan pyrrolase activity by increasing hepatic [NADPH], whereas subsequent withdrawal enhances pyrrolase activity by a hormonal-type mechanism. 2. It is now shown that this enhancement is associated with an increase in the concentration of serum corticosterone. 3. Chronic administration of the above drugs enhances, whereas subsequent withdrawal inhibits, brain 5-hydroxytryptamine synthesis. Under both conditions, tryptophan availability to the brain is altered in the appropriate direction. 4. The chronic drug-induced enhancement of brain tryptophan metabolism is reversed by phenazine methosulphate, whereas the withdrawal-induced inhibition is prevented by nicotinamide. 5. The chronic morphine-induced changes in liver [NADPH], pyrrolase activity, tryptophan availability to the brain and brain 5-hydroxytryptamine synthesis are all reversed by the opiate antagonist naloxone. 6. It is suggested that the opposite effects on brain tryptophan metabolism of chronic administration and subsequent withdrawal of the above drugs of dependence are mediated by the changes in liver tryptophan pyrrolase activity. 6. Similar conclusions based on similar findings have previously been made in relation to chronic administration and subsequent withdrawal of ethanol. These findings with all four drugs are briefly discussed in relation to previous work and the mechanism(s) of drug dependence.

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